AU689195B2 - Indole derivatives as 5-HT1 agonists - Google Patents

Description

-p -lr WO 95/20588 PCT/GB95/00142 1 INDOLE DERIVATIVES AS 5-HTI AGONISTS The present invention is concerned with new chemical compounds, their preparation, pharmaceutical formulations containing them and their use in medicine, particularly the prophylaxis and treatment of migraine.

Receptors which mediate the actions of 5-hydroxytryptamine (5-HT) have been identified in mammals in both the periphery and the brain. Currently, as many as seven 5-HT receptor classes are proposed (Hoyer et al,, Pharmacol. Rev., 46, 157-203, 1994), although only the classes nominated 5-HT 1 5-HT 2 5-HT 3 and 5-HT 4 have established physilogical roles.

European Patent Specification 0313397 describes a class of 5-HT agonists which act selectively at a particular subtype of 5-HT 1 receptor and are effective therapeutic agents for the treatment of clinical conditions in which a selective agonist for this type of receptor is indicated. For example, the receptor in question mediates selective cranial arterial vasoconstriction and inhibition of plasma protein extravasation into the dura mater evoked by activation of the Vth (trigeminal) nerve. The compounds described in the European specification are therefore beneficial in the treatment or prophylaxis of conditions wherein these actions are indicated, for example, migraine, a condition associated with and/or neurogenically-evoked inflammation' dilation of the cranial vasculature. However, it is within the scope of the earlier application that the target tissue may be any tissue wherein action is mediated by 5-HT 1 receptors of the type referred to above.

EP-A-0486666 discloses a class of compounds having exceptional activity at the 5-HT 1 receptor mentioned above and excellent absorption following oral dosing. These properties render the compounds particularly useful for certain medical applications, notably the prophylaxis and treatment of migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as "migraine", There has now been discovered a class of compounds which not only demonstrate improved metabolic stability and the necessary 5HT 1 receptor agonism, but also display a potentially selective inhibition of neurogenic inflammation and the nerve pathways responsible for the transmission of head pain. The compounds also display partial agonism at the 5HT 1 receptor and thus may have reduced side effects compared to previously known 5HT 1 receptor agonists.

SUBSTITUTE SHEET (iULE 26) I 1(\0[,0I0401'MBSIO 6 1I1I2 -2- Thus, according to a first aspect of the present invention there is provided a compound of formula

H

W \N

(CH

2 (I)

NRR'

wherein R and R' are each independently hydrogen or alkyl or R and R' are linked to form an azetidine ring; A is C3.6 cycloalkyl or C.

3 alkyl-C.

6 cycloalkyl; n is an integer of from 0 to 3; to. W is a group or (ii):

NR

2

X

x R N (ii) wherein R 2 is hydrogen or C 4 alkyl; t X is -NH- or -CHi-; t Y is oxygen or sulphur; and the chiral centre is in its or form or is a mixture thereof in any proportions; and salts, solvates and physiologically functional derivatives thereof; Compounds of formula wherein A is C 3 6 cycloalkyl are particularly suitable, Preferably, R and R 1 are each independently hydrogen or C 1 4 alkyl.

1 h~CI r.C O I I re I I WO 95/20588 PCT/GB95100142 3 In suitable compounds of Formula W is a five or six-membered ring containing from 1 to 3 hetro atoms independently selected from nitrogen, oxygen and sulphur, said ring being optionally substituted by one or more substituents independently selected from C1-4 alkyl, C3.

8 cycloalkyl, carbonyl or sulphonyl and optionally said ring is fused to a phenyl ring; or W is a group SO 2

NR

6

R

7 wherein R 6 and R 7 are independently hydrogen or C 1 -4 alkyl.

Particularly suitable compounds of formula include those wherein: R and R 1 are each independently hydrogen or C 1 4 alkyl; A is C 3 6 cycloalkyl; n is an integer of from 0 to 3; W is a five or six-membered ring containing from 1 to 3 hetero atoms independently selected from nitrogen, oxygen and sulphur, said ring being optionally substituted by one or more substituents independently selected from C1.

4 alkyl, C3.

8 cycloalkyl, carbonyl or sulphonyl and optionally said ring is fused to a phenyl ring; or W is a group SO 2

NR

6

R

7 wherein R 6 and R 7 are independently hydrogen or C 1 .4 alkyl; and salts solvates and physiologically functional derivatives thereof; with the proviso that said compounds are not 3-[cis-1 -(N,N-dimethylamino)cyclobutan-3-yl]-5-(,2,4-triazol--ylmethyl)-H-indole or 3-[trans-1 -(N,N-dimethylamino)cyclobutan-3-yl]-5-( 1,2,4-triazol-1 -ylmethyl)-H-indole Compounds of formula wherein A is C 3 or C 4 cycloalkyl are particularly suicable, with compounds wherein A is C 4 cycloalkyl being preferred.

Accordingly, in a second aspect the oresent invention provides a compound of formula (Ia): SUBSTITUTE SHEET (RULE 26) I 1 -~-rsl pqe~ I I PCTGB9IOO 142 WO 95/20588 Wa (1a) RaRa 1 wherein Ra and Ral are each independently hydrogen or C 1 4 alkyl; n is an integer of from 0 to3; Wa is a five or six membered ring containing from I to 3 hetero atoms independently selected from hitrogen, oxygen and sulphur, said ring being optionally substituted by one or more substituents independently selected from C 1 4 alkyl, C3-8. cycloalkyl, carbonyl or suljihonyl and optionally said ring is fused to a phenyl ring, or Wa is a group SO 2

NR

8

R

9 wherein R 8 and R 9 are independently hydrogen or C 1 4 alkyl; and sialts, solvates and physiologically functional derivatives thereof, witb Ile proviso that said compound is not 3 I-(N,N-dimethylamino)cyclobutan-3 ,2,4-triazol- I -ylmethyl)-H--indole or 3 -[Ernm-l1-(N,N-dimethylamino)cyclobutan-3 ,2,4-triazol- 1-ylmethyl)-H-indole W in. formula or Wa in formula (Ia) includes the following groups (iii), (vii), (viii) or (ix): (ii) I I (iii)

Y

SUBSTITUTE SHEET (RULE 26) WO 95/20588 PTG9/04 PCT/GB95100142

N-F

R

N (v

R

2 N-S0 2 (Vi) (ix) (Vii) (Viii) wherein R 2

R

3 and R 4 are hydrogen or C 1 4 alkyl;

R

5 is hydrogqn or NRI k1 1, wherein RI 0 and RI I are hydrogen or C 1 4 alkyl; E is or N; F is N when E is or F is when E is N; X is -NH- or -H- Y is oxygen or sulphur, Z is -NH- or and B is C 3 cycloalkyl and the chiral centre in formula or (ii) is in its or form or is a mixture thereof in any proportions; Suitably X is Further suitable groups W or Wa are those in which Y is oxygen, Preferred groups W and Wa are those of formulae and A particularly preferred group W or Wa is that of formula wherein X is Y is oxygen and R 2 is hydrogen.

Examples of preferred compounds of the invention include:- 4-[3-(trans-3 -aminocyclobutyl)- IH-indol-5-ylmethyl]-(4S)oxazolidin-2-one.

4-[3 -(trans-3 -aminocyclobutyl)- 1H-indol-5-ylmethyl] -(4S)oxazolidin-2-one acetate.

4-[3 -(gis-3 -amninocyclobutyl)- IH-indol-5-ylmethyl] -(4S)oxazolidin-2-one acetate.

4-[3 -(trans-3 -dimethylaminocyclobutyl)- IH-indol-5-ylmethyl]-(4S)oxazolidin-2-one, SUBSTITUTE SHEET (RULE 26) WO 95/20588 PcT/Gfl95100 142 6 (5,5iiethyl)4-3(2-faieflhy1 thmineeyelebut)14-ind1-5 yl] ethyl) imidazolidin-2,4-dione -(tran-3 -dimethylami~nocyclobutyl)- 1H-indol-5-yl]ethyI inhiolidin-2,4dione.

3- -(iran.s-3-arninocyclobutyI)- IH-indol-5- 1 yl) 2,4-dione.

2- {2-[3-(trans-3-dimethylamin9.y~ obujtyl)- 1 H-indol-5-yl] ethyl) phthalarnide.

3 -(trans- 3 -dimetyaih ocyclobutyl)- 1 H-indol-5-yl] ethyl) -3 e-2, 4-dione.

N-methy. -yI~ebhanesulphona mid& 4-[3-(trans-3-dimntthylaminocyclobutyI)- I H-indol-5-ylmethyl]-(4R)oxazolidin-2-one.

4[3 -(trans-3-dimethylam~inocyclobuty1)- 1H-indol-5-ylmethyll-3 -methyl(4S)oxazolidin-2-one.

ylmethyl]imidazolidin-2,4-dion-e 5-[3-(trans-3 -dimethylaminocyclobutyl)- 1 H-indol-5-ylmethyl] oxazolidin-2-one.

4-[3 -(trans-3-diniethylaniinocyclobut- I -ylmethyl)- (4S)oxazolidin-2-one.

4-[3 -(trans-3-methylaminocyclobutyl)- 1 H-indol-5-ylmethyl]-(4S)oxazolidin-2-one.

4-r3 -(trans-3 -dimethylaminocyclobutyl)- 1H-indol-5-ylmethyl]-3-methyl(4R) oxazolidin-2-one, -3-(tgans)-3-dimethylaminocyclobutyl) I H 4-[3 ijs-3-dimethylaminocyclobutyl- 1H-indol-5ylmethyl]-(4S)oxazolidin-2-one.

5-phenexy-3 OTans-3-aninGcyclobuty1--H-indo.

5-phenoxy-3-OLrns-3-dirnethylaminocycIlbtffy)-1 H-indole, N-benzyl-3 -(trais- 3 -dimethylamine yclobutyl)- 1H-indol-5-yi acetamide.

5-N-benzylcarboxamdo-3- rans-3 -dimethylaminocyclobutyl)- 1H-indole.

3 -methyl-5-[3 t s-3-dimethylaxninocyclobutyl)indol-5-yI]-1I,2,4-oxadiazole.

3-meth 3-(trns- 3 -dimethylaminocyclobutyl)indol-5-ylmethyl]- 1,2,4-oxadiazole.

transt~riGI5-4 3 l- (S)-2-(5-(2-Oxo-4-oxazolidinylmethyl)- 1H-indol-3-yl)cyclopropylamine.

csboxaido3 (Ytrans 3 dirnethylamineeyelobutyl) 1H-indole.

SUBSTITUTE SHEET (RULE WO 95/20588 PCT/GB95/00142 7 Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, ie basic, compounds. Such salts must clearly have a physiologically acceptable anion. Suitable physiologically acceptable salts of the compounds of the present invention include those derived from acetic, hydrochloric, hydrobromic, phosphoric, malic, maleic, fumaric, citric, sulphuric, lactic, or tartaric acid.

The succinate and chloride salts are particularly preferred for medical purposes. Salts having a non-physiologically acceptable anion are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in nontherapeutic, for example, in vitro, situations.

According to a third aspect of the present invention, there is provided a compound of formula or (Ia) or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof for use as a therapeutic agent, specifically as a "5-HT -like" receptor 1 agonist, for example, as a carotid vasoconstrictor or as an inhibitor of neurogenic inflammation in the prophylaxis and treatment of migraine. As indicated, however, target organs for the present compounds other than the carotid vasculature are within the scope of the present invention.

The amount of a compound of formula or or a salt or solvate thereof, which is required to achieve the desired biological effect will depend on a 'number of factors such as the specific compound, the use for which it is intended, the means of administration, and the recipient. A typical daily dose for the treatment of migraine may be expected to lie in the range 0.01 to 5mg per kilogram body weight. Unit doses may contain from 1 to 100mg of a compound of formula or for example, ampoules for injection may contain from 1 to and orally administrable unit dose formulations such as tablets or capsules may contain from 1 to 100mg. Such unit doses may beadministered one or more times a day, separately or in multiples thereof. An intravenous dose may be expected to lie in the range 0.01 to 0.15mg/kg and would typically be administered as an infusion of from 0.0003 to 0.15mg per kilogram per minute. Infusion solutions suitable for this purpose may contain from 0.01 to When the active compound is a salt or solvate of a compound of formula the dose is based on the cation (for salts) or the unsolvated compound.

SUBSTITUTE SHEET (RULE 2) a lg~ I WO 95/20588 PCTGB9500142 8 Hereinafter references to "compound(s) of formula or will be understood to include physiologically acceptable salts and solvates thereof.

According to a fourth aspect of the present invention, therefore, there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of formula or (Ia) and/or a pharmacologically acceptable salt or solvate thereof together with at least one pharmaceutical carrier or excipient. These pharmaceutical compositions may be used in the prophylaxis or treatment of clinical conditions for which a "5-HT -like" 1 receptor agonist is indicated, for example, migraine. The carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or liquid and is preferably formulated with at least one compound of formula or (Ia) as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredient. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.

Possible formulations include those suitable for oral, buccal, parenteral (for example, subcutaneous; intramuscular, or intravenous), rectal, topical and intranasal administration.

The most suitable means of administration for a particular patient will depend on the nature and severity of the condition being treated and on the nature of the active compound, but, where possible, oral administration is preferred.

Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or nonr-aqueous liquids; or as oil-in-water or water-in-oil emulsions, Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a fiavoured base, such as sugar and acacia or tragacanth, and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.

Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are SUBSTITUTE SHEET (RULE 26) I~ sri il-a~ l 11 'VIT WI)MI 4620 95:M46 1511219 -9preferably administered intravenously, they may also be administered by subcutaneous or intramuscular injection.

Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.

Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof. The active ingredient is typically present in such formulations at a concentration of from 0.1 to w/w.

The formulations of the invention may be prepared by any suitable method, typically by 15 uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.

For example, a tablet may be prepared by compressing an intimate mixture comprising a 20 powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.

Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.

Thus, according to a fifth aspect of the present invention, there is provided a method for the preparation of a medicament for the prophylaxis or treatment of a clinical condition for which a "5-HT 1 -like" receptor agonist is indicated, for example, migraine, comprising the step of ;4 L I- P \OPI'I>\I'D I4620 95 346. S1I2/7 -9Abringing a compound of Formula or (Ia) into a form suitable for administration.

According to a sixth aspect, there is provided a method for the prophylaxis or treatment of a clinical condition in a mammal, for example, a human, for which a "5-HT-like" receptor agonist is indicated, for example, migraine, which comprises the administration to said 0 000.

00.0 0* 00 ICP-PI q II 111 1 WO 95/20588 PCT/GB95/00142 mammal of a therapeutically effective amount of a compound of formula or (la) or of a physiologically acceptable salt, solvate, or physiologically functional derivative thereof.

In a further aspect the invention provides a process for the preparation of compound of formula by reacting a compound of formula (II)

NHNH

2 (CH2)n wherein n and W are as hereinbefore defined, with a compound of formula (III)

NHZ

H

i rI/ wherein A is as hereinbefore defined and Z is a benzyloxycarbonyl group, to give a compound of formula I wherein R and R 1 are both hydrogen. The reaction is typically carried out by heating the compounds at a non-extreme temperature suitably in the range to 100 0 C and preferably at about 800C in the presence of an aqueous mineral acid e.g.

sulphuric acid and then removing the benzyloxycarbonyl group by refluxing in a polar solvent system, for example formic acid in methanol, in the presence of a catalyst such as palladium on carbon.

Compounds of formula (Ia) can be prepared by reacting a compound of formula (II) wherein W is Wa with a compound of formula (III) wherein A is cyclobutyl.

Standard N-alkylation methods may be used to convert compounds of formula or (Ia) wherein R and R 1 are hydrogen to corresponding compounds wherein R and/or R 1 are C 1 4 alkyl.

SUBSTITUTE SHEET (RULE 26) i ~r~ WO 95/20588 PCT/GB95/00142 11 Compounds of formula or (Ia) wherein R=RI=C 1 4 alkyl may be prepared from the corresponding compound wherein R=R 1 =H by methods of N, N-dialkylation well known to those skilled in the art, for example, by treatment with the appropriate aldehyde in the presence of a reducing system, for example, sodium cyanoborohydride acetic acid, in a polar solvent, such as methanol.

Compounds of formula or (Ia) wherein R or R 1

=C

1 4 alkyl may be prepared from the corresponding compound wherein R=R1=H by N-benzylation using benzaldehyde and a suitable reducing agent, for example sodium borohydride, in a polar solvent such as ethanol, followed by N-alkylation using a suitable agent, such as the appropriate dialkylsulphate, typically in the presence of a base, for example anhydrous potassium carbonate, in a polar aprotic solvent, such as DMF, and finally N-debenzylation, typically by catalytic hydrogenation using, for example Pd/C in a polar solvent such as ethanol.

Compounds of formula (III) may be prepared from the appropriate 3-methylenecycloalkane- 1-carboxylic acid (J.Amer.Chem.Soc. 1959, 81, p 2 72 3 by reaction with diphenylphosphorylazidate and benzyl alcohol as described in EP-A-0366059. Alternatively t-butyl alcohol, or 4-nitrobenzyl alcohol may be used. The reaction may be carried out in an aromatic solvent e.g. toluene, benzene, xylene or pyridine. Chlorinated solvents such as chloroform and 1,2-dichloroethane, and polar aprotic solvents, such as glyme and dimethylformamide are also suitable. The intermediate carbamate may also be prepared by reaction of the aforementioned acid to form the corresponding acyl azide and rearrangement to form the isocyanate. This isocyanate may then be reacted with an alcohol to form the carbamate.

Compounds of formula (III) are prepared from the intermediate carbamates by a hydroformylation reaction (also known as the Oxo reaction) with hydrogen gas and carbon monoxide gas in the presence of a suitable transition metal catalyst. Rhodium, ruthenium, cobalt or platinum catalysts may be used. Chlorotris (triphenylphosphine) rhodium and carbonylhydridotris (triphenylphosphine) rhodium are preferred catalysts. Suitable pressures of hydrogen are in the range 1-100 atmospheres and a pressure of approximately atmospheres is preferred. The pressure of carbon monoxide is suitably in the range 1-100 atmospheres and is preferably approximately IC atmospheres. The hydroformylation reaction may be carried out in an aromatic solvent, e.g. toluene, xylene or benzene; a nonaromatic hydrocarbon, e.g. hexane, heptane or petroleum fraction; or in a dipolar aprotic SUBSTITUTE SHEET (RULE 26) i- I WO 95/20588 PCTIGB95/00142 12 solvent such as dimethyl formamide, Toluene is the preferred solvent. The reaction can be carried out at a non-extreme temperature, suitably in the range 20-1000C, and is preferably carried out at approximately 700C.

Compounds of formula (El) are believed to be novel and accordingly, in an eighth aspect, the present invention provides novel intermediates of formula (III).

Hydrazines of formula (II) may be prepared according to the methods of Cripps et. al. J Amer. Chem. Soc. 81 (1959) p 2 72 3 and as described in EP-A-0486666. Further methods for preparing these hydrazines are described in the Examples hereafter.

For hydrazines of formula (II) wherein W is a group of formula (v) the heterocyclic moiety may be constructed using the methodology described in Lin et. al., J. Org. Chem., (1979), 44, p4160-4164.

A typical reaction scheme for the preparation of a compound of formula is as follows:- SUBSTITUTE SHEET (RULE 26) I- i 91 i I WO 95/20588PTG9IO4 PCVGB95/00142

I/

2

H

2

/CO

Rh.Cat.

(Mn) 1) Fischer Indole Synthesis 2) HCOOHIPd/C NaCNBH 3

/HCHO

Wherein Z berayloxy carbonyl SUBSTITUTE SHEET (RIULE 2) I~ ~II WO 95/20588 PCTIGB95/0142 14 An alternative route for synthesising compounds of formula or (Ia) is by reacting a compound of formula (II) with a compound of formula (IV) OMe

(IV)

BOCHN

wherein BOC represents a tertiary butoxycarbonyl group, to give a compound of formula (I) wherein R R 1 H and optionally converting that compound into a compound of formula wherein R and/or R 1 C1 4 alkyl by standard alkylation techniques as hereinbefore described.

The reaction is suitably carried out in the presence of an aqueous mineral acid e.g. sulphuric acid at a non-extreme temperature, typically in the range 50 to 100 0 C and preferably at about 80 0

C.

Compounds of formula (IV) may be prepared as follows. An amide of formula (X) MeO Me

(X)

A

OBn can be prepared by coupling the known 3-benzyloxycycloalkane-l-carboxylic acid M.

Maxim et al. Chem. Ber. 1957, 90, 1425 with N,O-dimethylhydroxylamine hydrochloride either via the acid chloride or by the use of amide coupling agents such as dicyclohexyl carbodiimide, N,N'-carbonyl diimidazole or diphenyl phosphoroazidate. The coupling may also be effected by the use of an activated ester or by means of a mixed anhydride. The use of the acid chloride is preferred. The acid chloride may be prepared by using thionyl SUBSTITUTE SHEET (RULE 26) i ii- l--ii I II 'ql IRIII L -L WO 95/20588 PCT/GB9500142 chloride, phosphorus pentachloride or oxaloyl chloride, but thionyl chloride is preferred.

Suitable solvents for the coupling include pyridine, toluene or acetronitrile or chlorinated solvents such as dichloromethane in the presence of a base e.g. pyridine. Dichloromethane is preferred.

An amine of formula (IX) MeO Me

(IX)

A

NH

2 can be prepared from the compound of formula by hydrogenolysis of the benzyloxy group using a transition metal catalyst and a source of hydrogen to form an intermediate alcohol. This alcohol is converted into a leaving group, for example by conversion into its tosylate or mesylate derivative, and i's then reacted with a source of azide ion to form the azide. Reduction of the azide using a transition metal catalyst and a source of hydrogen forms the amine of formula (IX).

Typical catalysts for the hydrogenolysis step include palladium on carbon, palladium hydroxide on carbon, palladium black and platinum oxide. Palladium hydroxide on carbon is preferred. Suitable sources of hydrogen include hydrogen gas at 1 to 100 atmospheres pressure, ammonium formate and formic acid. The preferred source of hydrogen is hydrogen gas at 15 atmospheres. The reaction is suitably carried out in an organic solvent such as ethanol, methanol, ethyl acetate or acetic acid and is preferably carried out in ethanol.

Formation of the tosylate or mesylate derivative chloride or methanesulphonyl chloride in the triethylamine or 4-dimethylaminopyridine, may be effected using p-toluenesulphonyl presence of a base such as pyridine, Suitable solvents include pyridine, SUBSTITUTE SHEET (RULE 26) r p Is- WO 95/20588 PCT/GB95/00142 16 dichloromethane and toluene. The use of p-toluenesulphonyl chloride in pyridine is preferred.

Sodium azide is the preferred source of azide ion and the reaction is suitably carried out in a polar aprotic solvent e.g. dimethylformamide, dimethyl sulphoxide or N-methylpyrrolidinone at an elevated temperature suitably in the range of 40-170oC. Preferably, the reaction is carried out in dimethylformamide at approximately 800C, Reduction of the azide is effected by the use of a transition metal catalyst such as palladium on carbon, palladium hydroxide on carbon, palladium black or platinum oxide in a suitable solvent e.g. an alcohol such as ethanol or methanol, containing a mineral acid such as hydrochloric acid or an organic acid such as acetic acid. Sources of hydrogen incude hydrogen gas at 1 to 100 atmospheres pressure, ammorium formate and formic acid. The reduction is preferably carried out using palladium hydroxide on carbon in ethanol containing acetic acid under 1 atmosphere of hydrogen.

The t-butyloxycarbonyl-enol ether of formula (IV) is prepared from the amine of formula (IX) by protecting the amine group, for example as its t-butyloxycarbonyl derivative, using a suitable reagent. The N,N'-dimethylhydroxylamide moiety is then reduced to the aldehyde using a hydride reducing agent. Wittig reaction of the aldehyde with a suitable reagent gives the compound of formula (IV).

The protection stage can be effected using reagents such as ditbutyldicarbonate or N- (tbutoxycarbonyloxy) succinimide in the presence of a solvent. Suitable solvents are organic solvents such as dichloromethane, toluene and dioxane. The reaction is typically carried out in the presence of an amine catalyst such as 4-dimethylaminopyridine.

The reduction of the N,N'-dimethylhydroxylamide moiety is typically carried out using, for example, lithium aluminium hydride, which is preferred, or diisobutylaluminium hydride in an organic solvent. Suitable solvents include toluene, tetrahydrofuran and diethylether.

Tetrahydrofuran is the preferred solvent and the reduction is preferably carried out at a temperature of approximately 0°C.

The Wittig reaction is carried out using, for example, methoxymethyltriphenylphos phonium bromide in the presence of a strong base but methoxymethyltriphenylphosphonium bromide SUBSTITUTE SHEET (RULE 26) i II~_II I WO 95/20588 PCT/GB95/00142 17 and strong base is preferred. Suitable bases are n-butyl lithium, sodium hydride, sodium amide or potassium tbutoxide, which is preferred. The reaction is typically carried out in a solvent. Suitable solvents are etheral solvents, e.g. tetrahydrofuran or glyme, or polar apotic solvents such as dimethylformamide. Tetrahydrofuran is the preferred solvent and the reaction is suitably carried out at 0-100 0 C and preferably at approximately 800C.

Intermediates of formula (IV) are believed to be novel and accordingly in a further aspect, the present invention provides compounds of formula (IV).

Compounds of formula (Ia) are prepared by reacting a compound of formula (IV) wherein A is cyclobutyl with a compound of formula (II) wherein W is Wa.

A typical reaction scheme is as follows SUBSTITUTE SHEET (RULE 26) -iilpl I N r~N

S.

S. S S u(ZHD)/ Z HNI

DOGHN

v Gxi) (TTFTA) (TTA)

'(TA)

ZHN

I-I

QUU

-81- I*-1 WO 95/20588 PCT/GB95/00142 19 Reagents: SOC12 /HN(OMe)Me, (ii) Pd/C/H 2 (iii) TsCl/pyridine, (iv) NaN 3 /DMF; Pd/C/H 2 (vi) (BOC) 2 0; (vii) LiAlH4; (viii) Ph 3

PCH

2 OMe/KOtBu; (ix) AcOH 25% eq.

Compounds wherein A is a cyclopropyl group can suitably be prepared by reacting a ccmpound of formula (V)

O

(V)

NHBOC

wherein BOC represents a tertiary butoxy carbonyl group with a hydrazine of formula (II).

Intermediates of formula are believed to be novel and accordingly, in a further aspect, the present invention provides compounds of formula A typical reaction scheme is as follows: SUBSTITUTE SHEET (RULE 26) p ill WO 95/20588 PCT/GB95/00142 COOH O NHCOOtBu (iv) O NHCOOtBu (v HO- NHCOOtBu I

H

(CH2) n W NBH2 Reagents N 2

CHCO

2 Et/(RhOAc) 2 (ii) KOH/H 2 0, (iii) DPPA/tBuOH/PhMe, (iv)

BH

3

/THF/H

2 0 2

DMSO/(COCI)

2 The aldehyde of formula may be prepared by oxidation of the alcohol Although this alcohol has been described in US Patent No, 4988703, no indication as to stereochemistry has previously been. We have now discovered methods whereby the alcohol may be prepared in its pure trans form. Thus, Curtius reaction of 2-ethylenecyclopropane carboxcylic acid, according to the methods described above for the preparation of compounds of formula (III), gives the carbamate product. In this case, the preferred alcohol is t-butylalcohol and trans-N-t-butoxycarbonyl-2-ethenylcyclopropylamine is isolated.

The trans-ethenyl compound so isolated is now converted into the terminal alcohol by a hydroboration reaction with oxidation of the intermediate borane by hydrogen peroxide.

Typical reagents include borane-solvent complexes, or sodium borohydride boron trifluoride etherate. The use of borane-tetrahydrofuran complex in tetrahydrofuran is preferred.

Oxidation of the alcohol to the aldehyde may be effected by organic or inorganic oxidants. Organic oxidants include oxalylchloride/dimethylsulphoxide, inorganic oxidants include chromium, manganese and molybdenum complexes. Mixed organic/catalyst systems SUBSTITUTE SHEET (RULE 26) I IC LI WO 95/20588 WO 9520588PCTGB9IOO 142 21 such as N-methyl-morpholine-N-oxideltetrapropylammonium perruthenate are also suitable.

The preferred oxidant system is oxalylchloride/dimethylsulphoxide (known as the Swern oxidation), Suitable solvents include chlorinated and non-chlorinated organic solvents, Dichloromethane is preferred.

An alternative scheme for the synthesis of compounds of formula or (Ia) wherein one of R or RI is hydrogen with the other being C 1 4 alkyl is as follows: H H NCbz NCbz NCbz A4 0EtWO Ot Eto/<OEt (iii)I C 2)

W

(1 (Nv) Reagents: (EtO) 3 CH~pTsOHL Pd(OH) 2 /1 O%HCOOHIMeOH reflux (ii) NaN/RI, (iii) 1%H 2 S0 4 /80 0 .hewnvntion Aqll no Pe escA. "ORae b' way' OP illustrationMJN on)' NIB W11e 93Al g exampes The aldehyde of formula (III) may be protected as a dialkyl acetal derivative where the alkyl group may be Cl-C 5 and may be alicyclic or cyclic. The diethylacetal is preferred, The protection may be effected by reagents such as trialkylorthoformates or dialkoxypropanes in _4 SUBSTITUTE SHEET (RULE 26) I \Ofi'R\PDU\l4MO.5,346 1511207 22 the presence of an acid catalyst such as organic or mineral acids or Lewis acids.

Triethylorthoformate in the presence of p-toluene sulphonic acid is preferred.

The acetal may be alkylated using a base and a suitable alkylating agent. Suitable alkylating agents include alkyl halides, alkylsulphonates or dialkylsulphates. Methyl iodide is the preferred alkylating agent. Suitable solvents for the reaction include polar aprotic solvents, etheral solvents and alcohols. Dimethyformamide is preferred. The alkylated acetal may now be reacted with a hydrazine of formula (II) as described above and the carbamate protecting group removed to give the monoalkylated product.

The invention will now be described, by way of illustration only, by the following examples.

Example 1: 4-[3-(trans-3-aminocyclobutyl)-5-indolylmethyl)-(4S)-oxazolidin-2-one and 4- [3-(cis-3-aminocyclobutyl)-5-indolylmethyl)-(4S)-oxazolidin-2-one acetate.

cis and trans N-Methoxy-N-methyl-3-benzyloxycyclobutane-l-carboxamide (1)

I

To 3-benzyloxy cyclobutane-l-carboxylic acid (8.23 g, 39.95 mmol) was added thionyl chloride (50ml) and dimethyl formamide (2 drops). The reaction was refluxed 20 for 2h then the thionyl chloride removed on a rotary evaporator. The acid chloride *e t was dissolved in dichloromethane (50ml) and cooled to O0C. The N,O-dimethyl ohydroxylamine hydrochloride (4.29g, 44 mmol) was followed by pyridine (9.71g, S100 mmol). The reaction was allowed to warm to r.t. and stirred overnight. The

S

volatiles were removed on a rotary evaporator and the residue taken up in 10% aq.

hydrochloric acid and extracted with ethylacetate. The extracts were washed with water and dried over sodium sulphate.

Column chromatography gave the product (7.7g, 31mmol, 77%) as a clear oil.

HRMS for C 1 H, NO3, calculated 249.13649 found 249.1354.

b) i n BClI P \U0q11LWW fl\14610 9.5346 15/12/(J7 22A cis and trans 3-hydroxy-N-rrtthoxy-N-methyI cyclobutane-l-carboxamide The benzyl ether (7.7g, 30.9 mmol) in ethanol (250m1) was hydrogenated over palladium hydroxide on carbon (1g) at 15 atm H.2, The product was purified. by column chromatography to give 4.02g, 23.2 mmol, 82%. H-RMS for C 7

H

13 N0 3 calculated 159.08954 found 159,0892.

a a a. a a a *0 e.

a..

a.

0a a a a a a a a a a.

LllYII WO 95/20588 PCT/GB95/00142 23 cis and trans 3-Azido-N-methoxy-N-methylcyclobutane-l-carboxamide To the alcohol (4.02g, 25.2 mmol) in pyridine (40ml) at 0°C was added the ptoluensulphonylchloride (5.29g, 27.7 mmol) and the reaction stirred for 16 hrs. The volatiles were removed on a rotary evaporator ar, the residue taken up in ethyl acetate (150ml) and washed with 3% aq. hydrochloric acid in sat, brine (2 x 100ml), sat. aq sodium bicarbonate (50ml) and dried over sodium sulphate. Chromatography gave 7,47 g, 23.1 mmol, 92% oftosylated compound which was used directly for the next stage.

To the tosylate in dimethylformamide (40ml) was added the sodium azide (1.49g. 23 mmol) and the reaction heated to 80 0 C for 4 h. An additional amount of sodium azide (0.75 g, 11.5 mmol) was added and heating continued for 2hr. The cooled reaction was poured into water (200 ml) and extracted with ethyl acetate. The extracts were dried over sodium sulphate. Column chromatography gave the product (4.1g, 22.3mmol, 88%) as an oil. HRMS for C 7

H

12 0 2 calculated 184.09603 found 184.977.

cis and trans 3-Amino-N-methoxy-N-methlcyclobutane- I-carbonamide The azide (4.1g, 22.3mmol) in ethanol (oOml) and acetic acid (2ml) was hydrogenated (1 atm H 2 over 10% palladium on carbon (100mg). Column chromatography gave the product (1.28g, 8.1mmol, 36%) as an oil. HRMS for

C

7

H

12

N

2 0 2 calculated 158.10553 found 158.1033.

cis and trans 3- 1 butoxycarbonylamino-N-methoxy-N-methyl-l-cyclobutane carboxamide To the amine (1.28, 8.1 mmol) and 4-dimethyl aminopyridine in dichloromethane was added di t butylcarbonate (3.54g, 16.2 mmol) in one portion and the reaction stirred for 16 hr. Water (50ml) was added and the reaction stirred for min. The dichloromethane was separated and dried over sodium sulphate. Column chromatography gave the product as an oil (1.46g, 5.66mmol, Microanalysis calculated C 55.81, H 8.53, N 10,85, found C55.62, H 8.87. N 10.49.

cis and trans 3-t butoxycarbonylamino-cyclobutane-1-carboxaldehde SUBSTITUTE SHEET (RULE 26) -i i i I -CI ICl r-- Pb -I I WO 95/20588 PCT/GB95/00142 24 To the methoxymethylamide (258mg, Immol) in tetrahydrofuran (5ml) at -50 0 C was added di isobutyl aluminium hydride (1.1 mol of a 1 M solution in toluene) and the reaction allowed to warm to 0 0 C for 30min, then water (20ml) added. The mixture was extracted with ethyl acetate and the extracts dried over sodium sulphate.

Column chromatography gave the pure product. Microanalysis calculated C 60.30, H 8.84, N 7.04 found C 60,30, H 8.87, N 7,02.

cis and trans N-t butoxvcarbonvl-3-(2-methoxvethenvyl)cvclobutane-1-amine.

To methoxymethyltriphenyl phosphonium bromide/sodium amide (0.23 mmol) was added tetrahydrofuran (5ml) and the reaction stirred for 30 min. The aldehyde 0.151 mmol) in tetrahydrofuran (0.5m) was added dropwise and the reaction heated to 80 0 C for 4hr. The cooled reaction mixture was poured into water and extracted with ethyl acetate (2 x 20ml). The extracts were dried over sodium sulphate. Column chromatography gave the product. (14.3 mg, .063 mmol, 42%) as an oil.

4-r3-(trans-3-aminocyclobutyl)-5-indolvlmethyl)-(4S)-oxazolidin-2-one acetate. and 4-r3-(cis-3-aminocvclobutvl)-5-indolvmethyll-(4S)-oxazoli'din-2-one acetate.

To the appropriate hydrazine (310mg, 1. 5mmol) in 1% aq sulphuric acid (I 0ml) was added the methylenol ether mmol) and the reaction heated to 80'C for 6 hrs, The reaction was cooled and washed with ethyl acetate, The acidic layer was saturated with sodium chloride and extracted with tetrahydrofuran, the extracts were dried over sodium sulphate. Column and HPLC chromatography gave the trans product (gum) HRMS calculated for C 16

H

19

N

3 0 2 285.14773 found 285,1477 and the cis product mpt 180-181 0 C IRMS calculated 285.14773 found 285.1458.

Example 2: Trans-4-r3-(3-(dimethlaminocclobutvl)-5-indolvlmethyll-(S)-1.3 oxazolidin-2-one Trans-N-(benzvloxv carbonvl)-cclobutanamine-3-acetaldehyde SUBSTITUTE SHEET (RULE 26) i I---I I1IP I WO 95/20588 PCT/GB95/00142 Trans-N-(benzyloxycarbonyl)-3-methylenecyclobutanamine (18g, 83 mmol)(prepared as described in EP-A-0366059) and tris(triphenylphosphine)rhodium chloride (400 mg 0.43 mmol) were heated to 0 C in toluene (250ml) under 100 atmospheres of CO:H 2 (1:1 mixture for 18 hrs.

The solvent was evaporated under reduced pressure and the residue chromatographed on silica eluting with 25% ethylacetate in cyclohexane. First product eluted mixture of cis and trans branched chain aldehydes, Second product eluted mixture of cis and trans straight chain aldehydes, the trans isomer was crystallised from ether as white needles (mpt 66-67 0 Microanalysis for C 14

H

17 N0 3 Calculated C 68.02, H 6.88, N 5,67 Found C 67,92, H 6.90, N 5.63.

4-[3-(trans-3-aminocyclobutyl)-1H-indol-5-vlmethyl-(4S)-oxazolidin-2-one The appropriate hydrazine (6.3g, 30mmol) and trans-N- (benzyloxycarbonyl)cyclobutanamine-3-acetaldehyde (6.3g, 25.5mmol) were heated to 800C for 7 hours in 1% sulphuric acid (aq) (100ml) and ethanol (150ml). The reaction mixture was evaporated in vacuo and brine added. Extraction with ethyl acetate gave the crude product (10.5g, 83%) MS (FAB) 420 (M+1) The product from the above was refluxed in 10% formic acid-methanol with palladium hydroxide on carbon (Ig) for 7 hours. The solvent was removed in vacuo and brine added. The solution was then washed with ethyl acetate and then made basic (pH 10-12) with dil. ammonium hydroxide solution. Extraction with THF gave the crude product which was purified by flash chromatography (2:14:84 NH 3

ETOH

3 (2g, 28%) MS (FAB) 286 (M+1) Trans-4-r3-(3-dimethylaminocvclobutvl)-5-indolvlmethyll-(S)-1,3-oxazolidin-2-one Formaldehyde (0.18 ml, 2,22 mmol) in methanol (5 ml) was added to the product of step (250 mg, 0.88 mmol), acetic acid (0.26ml, 4.55 mmol) and sodium cyanoborohydride (70mg, 1.17 mmol) in methanol (15ml) and stirred at room temperature under a nitrogen atmosphere overnight.

SUBSTITUTE SHEET (RULE 26) I Ii I I I I Ir I WO 95/20588 PCT/GB95/00142 26 Water was added and the mixture washed with ethylacetate. The aqueous phase was then adjusted to pH 10 with potassium carbonate and saturated with sodium chloride, Extraction with ethylacetate gave a sticky gum which was chromatographed on silica eluting with 1% 0.88 NH 3 solution in methanol to give an off white powder. Elemental analysis for C18 H 23

N

3 02 0.35 CHC13 Calculated C 62.05, H 6.63, N 11.83 Found C 62.21, H 6,76, N 11.55 mpt Becomes gummy at 77-78 0

C.

This solvated compound can be dried in vacuo at 80 0 C to provide the anhydrous compound of Example 4.

The following compounds were made by selecting appropriate starting materials and following the method described in Example 2.

SUBSTITUTE SHEET (RULE 26) I i 4 ~1 wo 95/20588 WO 9520588PCTGB95OO 142 SUBSTITUTE SHEET (RULE 26) WO 95/20588 PTG9/04 PCT/GB95/00142 -f 9. 1 cyclobutyl Me Me trans M.pt, 106- 1090C N-

N-

dec. H

SO

2 NHMe I cyclobutyl Me Me trans M. pt 220- 220C *11. 0 1 cyclobutyl Me Me (R) M.pt. trans 163-

N

165 0 C :H 12. 1 cyclobutyl Me Me trans M.Pt.

70-72 0 C

N-

N

H

0 SUBSTITUTE SHEET (RULE 2)

I

WO 95/20588PCIB5O12 PCT/GB95/00142 13), 01 cyclobutyl Me Me M.pt. trans fosmn

N

;:Me 14. CONH 2 0 cyclobutyl Me Me trans M~pt.

93-95C 01 cyclobutyl Me Me (S)-cis Hlygro- *DiIl SCOJ2iC

N

H

16. OPh 0 cyclobutyl H H trans M~pt, 164- 1660C__ 17, OPh 0 cyclobutyl Me Me trans M.pt.

M

189- 190 SUBSTITUTE SHEET (RULE 26) WO 95/20588PCGBIO14 PCT/GB95/00142 18. N 0 cyclobutyl Me Me trans M.pt. foam MeN 19. 1 methyl Me Me (S) M'pt. icyclobutyl trans foamN 0 Me- Example 20: Alternative synthesis for 4-r3-(Trans-3-m inocvclobutvl)-5- indolvimethylloxazolidin-2-one: Comr)ound of Examnle

I

The trans-N-(benzyloxycarbonyl)-cyclobutanami~ne-3-acetaldehyde (1 g, 4 mnmol) and hydrazine (1.2g, 5.8 mm ol) were heated to 80'C in 1% aqueous sulphuric acid for 6 hours. After cooling the solid was filtered off' and dried under vacuum.

Used crude for next stage. mpt 95-100'C. The Cbz protected indole (500mg, 1 .2mmol) and palladium hydroxide on carbon (50mg, 0.36 mnmol) were refiuxed in formic acid in methanol (25m1) for 3 hours. The catalyst was filtered off and the solvent evaporated under reduced pressure. Brine was added to the residue and the pH adjusted to 11 with 0.88 ammonium sou3.The milky solution was extracted with tetrahydrofuran, dried over MgSO 4 and tvaporated under vacuum to give the free base as a foam. HRMS Calculated 285,1477. Found 285,1485.

Example 21: -trans-3-dimnethylaminocvclobutyl)- oxazolidin--2-one 5-benzyl-2-oxazolidinone 2,3-Epoxypropylbenzene (60g, 448 mmol) and potassium cyanate (70g, 364 mmol) were refiuxed in DMF (600m.1) and water (300m.1) for 4 hours, The solvent was SUBSTITUTE SHEET (PULE 26) I WO 95/20588 PCT/GB95/001,12 31 evaporated in vacuo and water added. The aqueous was then extracted with ethyl acetate, dried (Mg SO 4 and evaporated, Recrystallization from ethyl acetate gave the product (28.2g, 36%) Mpt 106-1070C MS (EI) 177 133, 86.

5-.(4-nitrobenzyl)-2-oxazolidinone 4-benzyl-2-oxazolidinone (5g, 28mmol), potassium nitrate (2.9g, 29 mmol) and piodotoluene (0.5g, 2 mmol) were stirred in trifluoracetic acid (50ml) overnight. The mixture was then poured onto ice and extracted with ethyl acetate. This was washed with sodium bicarbonate solution, dried (Mg SO 4 and evaporated. Flash chromatography (70:30 ethyl acetate/hexane) gave the product (2.2g, 35%) Mpt 150-151oC, MS (ES) 223 1)+ 5-(4-aminobenzyl)-2-oxazolidinone 4-(4-nitrobenzyl)-2-oxazolidone (9,9g, 45 mmol) and 10% palladium on carbon (900 mg) were stirred under a hydrogen atmosphere in methanol (200ml) and 2.5N aq.

HCI (50ml) at room temperature for 4 hours. The reaction mixture was filtered and evaporated. Water was added and the solution washed with ethyl acetate. The aqueous phase was then basified with dil NaOH solution and extracted with THF to give the crude product (6.2g, 72%) Mpt 135-1380C MS(EI) 192 106, The 5-(4-aminobenzyl)-2-oxazolidinone (1.7g, 8.9 mmol) was disolved in c.HCI (2ml) and water (7,5mnl) and then cooled to below 50C. A solution of sodium nitrite (0.61g 7 mmol) in water (7.7mi) was then added dropwise. The solution was then stirred at 5°C for 20 minutes. This was then added slowly to a cooled solution (below 5 0 C) of sodium sulphite (3.4g, 27 mmol) in water (15 ml). The solution was stirred for 20 minutes before allowing it to warm to room temperature and then heating slowly to 600C. c.IIC (3ml) was then added and heating at 600C continued overnight. The solution was then diluted with water (15ml) and ethanol Trans-N-(benzyloxycarbonyl) cyclobutanamine-3-acetaldehyde (1.5g, 6mmol) was then added and the mixture heated to 800C for 7 hours. Partial evaporation followed by extraction with THF gave the crude product which was purified by flash chromatography (5:95 methanol/chloroform) (1.7g, 46%) MS (FAB) 420 SUBSTITUTE SHEET (RULE 26) i ~L PCTIGB95/00 142 WO 95/20588 32 The product of this step was then treated by methods outlined in example 2 to provide (±-5-jj3 -(rans-3 -dimethylami nocyclobutyl)- 1H-indol-5-ylmethyl]oxazo- lidin -2-one.

Examnple 22: 4-r3 -(trans-3 -methylaminocyclobutyl)- 1H-indol-5-ylmethyll-(4S)oxazolidin-2-one Trans-N-(benzyloxycarbonyl) cyclobutanamine-3-acetaldehyde diethyl acetal.

Trans-N-(benzyloxycarbonyl)cyclobutanami ne-3 -acetaldehyde (1 g, 4 mmol), triethylorthoformate (1.35m1, 8 mmol) and p-toluene suiphonic acid (100mg) were refluxed in ethanol for 3 hours. The reaction mixture was evaporated in vacuc and purified by flash chromatography (10:90 Ethyl acetate/cyclohexanone) to give a colourless oil (1.2g, 94%).

Trans-N-benzyloxycarbonyl-N-methyl cyclobuftanamine-3'-acetaldehyde diethyl acetal.

Trans-N-(benzyloxcycarbonyl) cyclobutanamine-3-acetaldehyde diethyl acetal (1 .2g, 3.7 mmol) in dry DMF (l0nmi) was added dropwise to a cold suspension of sodium hydride (60% in oil) (165mg, 4.lmmol) in dry DMF (l0mi). After the addition was complete the mixture was allowed to stirred at 100'C for 1/2 hour. Methyl iodide (0.23m1, 3.7 mmol) in dry DMI (5m1) was then added dropwise. The mixture was then allowed to warm to room temperature and stir for 2 hours. The reaction was then poured onto ice and extracted with ether. Flash chromatography (10:90 ethylacetate/cyclohexane) gave the product as a colourless oil (1g, 83%).

The product of this step was then treated by methods outlined in example 2 to provide 4-[3-(trans-3 -methylaminocyclobutyl)- 1H-indol-5-ylmethyl]-(4S) oxazolidin-2-one.

Example 23: 5-N-benzvlcarboxanrido-3 -tans-3-dimethylaminocyclobutyl)- IH-indole 3-(trans-3-dimethylaminocyclobutyl) 1H-indole-5-carboxylic acid.

SUBSTITUTE SHEET (RULE 26) WO 95/20588 PCTGB9IOO 142 33 5-carboxamido-3-(trans-3 -dimethylami nocyclobutyl)- IH-indole (0.4g, 1 .6 mmol), prepared using the methods described in example 2, was refluxed in I OM NaOH solution (i5mI) and methanol (l0mi) for 7 hours. The resulting solution was cooled in ice and neutralized with dil HC1. This was then evaporated to dryness in vacuo and methanol added. The sodium chloride was filtered off and the solution evaporated to give the crude product.

5-N-benzylcarboxamido-3-trans-3-dimethylaminocyclobutyl)- IH-indole The crude 3-(trans-3-dimethylaminocyclobutyl)- 1H-indole-5-carboxylic acid (0.4g, 1.6 mmol), 1H-benzotriazol-1I-yl)-N,N,N 1

N

1 -tetramnethyluronium tetrafluoroborate (0.57g, 1.8 mmol), benzylamine (0.18m1, 1.6 mnxol) and triethylamine (0.25, 1.8 mmol) were stirred at room temperature in dry DMIF for 5 hours. The reaction was quenched with water and extracted with ethyl acetate. This was dried (MgSO 4 and evaporated to give the crude product which was purified by flash chromatography 10:89 0.88 NH 3 MeOK, CHCI 3 (175mg, 32%) MS(EI) 347 Example 24 2r3 -(frans-3-dimethvlaminocyclobul)- phthalamide The Cbz protected intermediate prepared by methods described in example 2, 1.6mmol), boron trifluoride etherate (2m1, 16 mmol) and ethylmercaptan (3.4nil, 46 mmol) were refiuxed for 48 hours, The mixture was then evaporated in vacuo and brine added. The pH was then adjusted to pHl0-12 with dii NaOH solution.

Extraction with THF gave the crude product which was chromatographed on silica eluting with 1:99 0.88 NF{ 3 /MeOT{. (190mg, 33%) MS (FAB) 360 The product of this step was then treated by methods outlined in example 2 to provide 2- 2- [3 -(trans-3 -dimethylaminocyclobutyl)- I H-indol1-5 -yl] ethyl)} phthalamide.

Example 25 3 -trans-3 -dimethylaminocvclobutyl] -1H-indol-5 -yI acetarnide 4-hydrazinophenylacetic acid hydrochloride.

SUBSTITUTE SHEET (RULE 26)

~IIPL-I

WO 95/20588 PCT/GB95/00142 34 To a solution containing conc. HCI (76ml) and 4-amino phenylacetic acid (10g: 66 mmol) at 4 0 C was added a solution of sodium nitrite (4.56g; 55 mmol) in water dropwise, while maintaining the temperature at 0 to 4°C. The mixture was stirred for 30 minutes and added to a cold (0 0 C) solution of SnCl 2 (74.5g 331 mmol) in conc. HCI (50ml). The mixture was left to warm to room temperature overnight. The precipitate formed was filtered and washed with water (50ml), aq.HCl (50ml), water (50ml) and ether (2 x 50 ml). The solid was dried in vacuo to give the product 13g. M.pt. 220-2230C dec.

MS. 166(M+) 151, 135, 121 NMR [360Mz, IH] ppm 3.5 2H) 6.9 2H) 7.1 2H), 10.7 (bs).

(b)3-[trans-N-(benzyloxycarbonyl)-3-aminocyclobutyl]-lH-indol-5-yl acetic acid.

To 4-hydrazinophenylacetic HC1. in 1% aq. sulphuric acid (75 ml) was added trans- N-(benzyloxycarbonyl)cyclobutanamine-3-acetaldehyde (5g, 20 mmol). The mixture was heated to 900C for 7 hours. The semi-solid formed was filtered and washed with 1% H 2 S0 4 and water. The solid was then taken up into ethyl acetate and washed with water. The organic phase was dried (MgSO 4 The product was obtained as a sticky solid. Yield: 6.5g (c)3-[trans-N-(benzyloxycarbonyl)-3-aminocyclobutyl]-lH-indole-5-ylacetamide.

To a solution of acetic acid (0.5g, 1.38 mmol) in DMF (5ml) was added 0-(3,4-dihydro-4-oxo-1,2,3benzotriazine-3-yl) N,N,N 1 ,Nl-tetramethyluronium tetrafluoroborate [TBTU] (0.44g; 1.38 mmol) and Et 3 N (0.21 ml: 1.52 mmol). Anhydrous ammonia was then bubbled through the solution for 1 hour at room temperature with cooling in ice as necessary. The mixture was stirred overnight at room temperature. The solvent was evaporated under vacuum. The residue was chromatographed on silica using MeOH (10%)/chloroform (89%)/880 NH 3 Yield 0.28g MS 269, 253, 182 NMR [360MH 3

H

1 2.49 4H) 3.3 2H), 3.55 (m 1H) 4.11 (m 1H); 5.0 (m 3H), 6.78 (bs 1H), 6.98 (dd 1.6HZ, 8.5 HZ; 1H) 7.3 7.7 (d 6.8 HZ, 1H).

SUBSTITUTE SHEET (RULE 26) WO 95/20588 C/B9/04 PCT/GB95/00142 The product of this step was thien treated by methods outlined in example 2 to provide 3-[irans-3-dimethylamino-yclobutyl]- IH-indol-5-yl acetamnide.

Example 26 N-benzyl-3-[frans-3 -dinethvlanlinocvclobutvll-l1H-iild4ol-5-yl acetamide.

N-benzyl-3-[trans-3-(benzyloxycarbonylamino)cyclobutyl]- acetainide To a solution of 3-[trans-N-(benzyloxycarbonyl)-3-aminocyclobutyl]indol-5-yI acetic acid (1g, 2.76 mmol) in DMF (Snil) was added TBTU (0.97g 3.04 mmol), Et 3

N

(0.42m1 3.04 nimol) and benzylarniine (0.33m1 3.04 mniol). The mixture was stirred overnight at room temperature. The solvent was evaporated Linder vacuum and the residue chromatographed on Silica 5% MeOI94% CHCI 3 880 NH3 to give a pale yellow oil, yield: 0.81g MS 468 392, 333.

The product of this step was then treated by methods outlined in example 2 to provide N-benzyl-3 -[trans-3-dimethylaminocyclobutyl]- 1 H-indol-5-yl acetamide.

Example 27: 3 -methyl-5-[34tIrans-3 -dimethylaminocyclobutyl)- 1 .2,4-oxadiazole.

N-[(dimethylamino)ethylidene]-3 -[trans-3 -(benzyloxycarbonylamidno)cyclobutyl]- To a solution containing 3-I[trans-N-benizyoxycarbonyl-3-aminocyclobutyl]indol-5-yI acetamide (4.68g 13 nimol) in toluene (l0mi) was added N,N-dimethyl acetamide dimethyl acetal (40m1). The mixture was then heated at 1200C for 2 hours under Dean Stark conditions. The solution becomes very dark. The solvent is evaporated under vacuum to give N-[(dimethylamino)ethanyidene]-3-[Lar.-3- (benzyloxycarbonylami no)cyclobutyl]- Yield 5.7g crude.

5- {3-[N-(benzylox ycarbonyl)-trans-3 -dimethylamiinocyclobutyl]- 1H-indol-5-yl 3-methyl-i ,2,4-oxadiazole SUBSTITUTE SHEET (RULE 26) BI~ WO 95/20588 PCT/GB95/00142 36 To a mixture containing hydroxylamine HCI, (10mg 1,6 mmol) N NaOH (0.2ml), pdioxane (3ml) and 70% acetic acid (10mi) was added the amidine (500mg 1.6 mmol) and the mixture heated to 1200C for 1 2 hours. The solvent was evaporated under vacuum and the residue was chromatographed using silica and 40% cyclohexane to give the product.

Yield: 150mg as a foam MS 417 296 The product of this step was then treated by methods outlined in example 2 to provide 3-methyl-5-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]- 1,2,4-oxadiazole.

Example 28: 3-methyl-5-f3-(trans-3-dimethvlaminocyclobutyl)- vlmethvll 1 ,24-triazole.

To a solution of the amidine, prepared as in example 2 7 above, (3g, 6.99mmol) in 70% aqueous acetic acid (100mi), was added hydrazine hydrate 10.9ml, 8.39mmol). The mixture was stirred at 900C for 5 hours. The mixture was concentrated under reduced pressure and diluted with water (100ml). The aqueous phase was extracted with ethyl acetate (2 x 50ml). The organic phase was dried (MgSO 4 and evaporated. The residue was chromatographed using MeOH/89% CHCI 3

/%NH

3 to give an oil.

Yield 200 mg MS 416 415 326 The product of this step was then treated by methods outlined in example 2 to provide 3-methyl-5-[3-(trans-3-dimethylaminocyclobutyl)- 1,2,4-triazole.

Example 29: (S)-2-(5-(2-Oxo-4-oxazolidinylmethyl)- 1H-indol-3 -l)cclopropylamine a) Ethyl 2-ethenylcyclopropane carboxylate Butadiene (200ml, Aldrich) condensed at -700 was transferred to a glass lined autor .ve vessel and ethyl diazoacetate (20g, 0.175 mol, Aldrich) and rhodium acetate dimer (0.3g, Aldrich) added. The suspension was stirred in a sealed autoclave for 24 hours at ambient temperature. The contents were diluted with 2% SUBSTITUTE SHEET (RULE 26) 3 1 I WO 95/20588 PCT/GB95/00142 37 diethyl ether in pentane and passed through a silica pad (50g). The pad was washed with a little ethanol and further ether-pentane. The eluant containing ethanol was treated separately. The organic phases were concentrated at reduced pressure and subjected to short path bulb to bulb disillation (90-1050 at 12mm) to give the product as a colourless liquid (14.6g).

b) 2-Ethylenecyclopropanecarboxylic acid The above ester (11.79g, 84.21 mmol) was dissolved in tetrahydrofuran (THF) (16ml) and treated with potassium hydroxide (7,32g) in water (75ml) and heated under gentle reflux for 5 hours. The reaction mixture was concentrated and the residue dissolved in water. This was acidified with cone. hydrochloric acid to pH 4 and the emulsion was extracted with diethyl ether. The organic phase was dried, concentrated and the residual oil distilled (100-1200 at 3mm) to give the product as a colourless liquid (8.7g).

c) trans-N-t-Butoxycarbonyl-2-ethenylcyclopropylamine The above acid (8.66g, 77.43 mmol) was dissolved in anhydrous toluene cooled to 00, treated with dry triethylamine (11.9ml) and then, dropwise, with diphenylphosphoryl azide (23.4g, Aldrich) in toluene (25ml). The solution was warmed to 800 and kept at 80-850 for 45 mins. Anhydrous t-butanol (36ml) and toluene (10ml) were added quickly and the solution heated at 1020 for 6 hours. The reaction mixture was allowed to cool and diluted with diethyl ether, washed with IN orthophosphoric acid (100ml), saturated aq.sodium bicarbonate and brine, dried and concentrated. The residual oil was purified by chromatography (silica: 350g; hexane: ethyl acetate 95:5) to give the product as a colourless oil (3.91g), d) trans-N-t-Butoxycarbonyl-2-(2-hydroxyethyl)cyclopropylamine The above alkene (3.91g, 21.37 mmol) in anhydrous THF (20ml) was cooled to 00 and treated with borane THF complex (42.7 ml, 1M in THF, Aldrich). Stirred at 00 for 2.5 hours then allowed to reach ambient temperature, recooled to -50 and treated sequentially with 6N aq.sodium hydroxide (24.8 ml) and 30% aq. hydrogen peroxide (7.53ml). The mixture was stirred at room temperature for 10 mins then SUBSTITUTE SHEET (RULE 26) WO 95/20588 38 treated with excess solid potassium carbonate and extracted with ethyl acetate (3 x 100ml) The organic phase was washed once with aq. orthophosphoric acid, aq.

sodium bicarbonate, brine and dried. The solvent was removed and residual oil subjected to chromatography (silica 300g; 1% to 4% methanol in dichloromethane) to give the product as an oil which crystallised upon standing at 30 (4 Ig) e) trans-N-t-Butoxycarbonyl-2-(2-oxo-ethyl)cyclopropylamine Oxalyl chloride (175ml) in dry dichloromethane (DCM (8ml) was cooled to -650 and treated with dimethyl sulphoxide (316mg) in DCM (Iml) and after 10 mins. the above alcohol (394mg, 1.96 mmol) in DCM (2ml) was added. After 1 hour at -650 triethylamine Iml) was added and reaction allowed to reach 00 and di: sted with diethyl ether (25ml). The organic phase was washed with water, IN orthophosphoric acid, satd.aq. sodium bicarbonate and brine and dried. The solvents were removed to give the product as a pale yellow oil (349mg), f) 2 2 -Oxo-4-oxazolidinylmethyl)-1H-indol-3-yl)cyclopropylamine The above aldehyde (349mg, 1.75 mmol) was treated with 3:1 water: acetic acid (25ml) and 4 -(2-oxo-4-oxazolidinylmethyl)phenylhydraLine (440mg, 2.12mmol) The mixture was heated under nitrogen at 80-850 for 5 hours. The reaction mixture was concentrated, DCM, ethanol, 880 ammonia (85:15:1) added and reconcentrated.

The residue was subjected to chromatography (silica: 50g; DCM, ethanol, ammonia (85:15-1) and the component (Rf. 0.10; silica-DCM, methanol, ammonia (90:101) isolated. The latter was subjected to purification (x2) by preparative HPLC (Zorbax Cg, MeCN 0.1M aq.NHOAc) to give the title compound as a yellow foam in the form of an acetate salt. NMR [360 MHz, 1H] (d 6 -DMSO): 0.80 1.74 (1H,m), 2.32 2.79 (1H,ddd), 2.91 (1H,dddd), 4.03 (2H,m) 4.29 6.88 (IH,dd), 6,92 (1H,dd), 7.22 (1H,d).

7 45(lH,s,2-H); 7.70 (IHs,NH); 10.57 (lH,s,indole NH) Accurate mass; 271.13208 (C 15

H

17

N

3 0 2 PHARMACEUTICAL FORMULATION EXAMPLES In the following Examples, the "active ing:edient" may be any compound of formula or (Ia) and/or a physiologically acceptable salt, solvate, or physiologically functional dervative thereof 19LP WO 95/20588 PCT/GB95/00142 39 Tablet formulations Oral Me/tablet A B Active ingredient 2.5 Avicel 13 Lactose 100.5 69.5 Starch (maize) 9 Sodium starch glycollate Povidone 3 3 Magnesium stearate 1 1 125 Formulations A to C may be prepared by wet granulation of the first six ingredients with the povidone, followed by addition of the magnesium stearate and compression.

(ii) Buccal Mg/tablet Active ingredient Hydroxypropylmethyl cellulose (HPMC) Polycarbophil 51.5 Magnesium stearate 1 SUBSTITUTE SHEET (RULE 26) i r r i r I I- WO 95/20588 PCT/GB95/00142 The formulation may be prepared by direct compression of the admixed ingredients.

Capsule formulations Powder Mg/Capsule D E Active ingredient 2.5 Lactose 175.5 Starch (1500NF) 45 139.5 Sodium starch glycollate Magnesium stearate 2 2 225 150 Formulations D and E may be prepared by admixing the ingredients and filling two-part hard gelatin capsules with the resulting mixture.

(ii) Liquid fill Mg/Capsule F G Active ingredient 2.5 Macrogol 4000 BP 222.5 Lecithin -110 Arachis oil 112.5 225 225 Formulation F may be prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling two-part hard gelatin capsules therewith. Formulation G may be prepared by dispersing the active ingredient in the lecithin and arachis oil and filling soft, elastic gelatin capsules with the dispersion.

SUBSTITUTE SHEET (RULE 26) ~IIP PCT/GB95/00142 WO 95/20588 (iii) Controlled release Mg/tablet Active ingredient Avicel Lactose Triethylcitrate Ethyl cellulose 145.5 62 225 The formulation may be prepared by mixing and extruding the first four ingredients and spheronising and drying the extrudate. The dried pellets are coated with ethyl cellulose as a release controlling membrane and filled into two-part, hard gelatin capsules, Intravenous injection formulation by weight Active ingredient Hydrochloric acid Citrate buffer) Water for Injections q.s to pH 7 to 100% The active ingredient is taken up in the citrate buffer and sufficient hydrochloric acid added to affect solution and adjust the pH to 7. The resulting solution is made up to volume and filtered through a micropore filter into sterile glass vials which are sealed and oversealed.

SUBSTITUTE SHEET (RULE 26) I rN WO 95/20588 PCT/GB95/00142 42 Biological Assays A: Rabbit Saphenous Vein Assay Compounds of formula prepared in Synthetic Examples 1 to 17 were each tested for their activity as agonists for their activity as agonists for the "5-HT 1 -like" receptor mediating smooth muscle contraction by the following method.

Right and left lateral saphenous veins were obtained from male New Zealand White Rabbits (2.4-2.7 kg) which had been killed by intravenous injection of pentobarbitone sodium mg/kg). Ring segments (3-5 mm wide) prepared from each vessel were suspended between two wire hooks and immersed in 20ml organ baths containing Krebs' solution (pH 7.4) of the following composition NaCI 118.41, NaHCO 3 25.00, KCI 4.75, KH 2

PO

4 1.19, MgSO 4 1.19, glucose 11.10 and CaCl 2 2.50. Cocaine (30pM) was present in the Krebs' solution throughout the experiment to prevent the uptake of amines by sympathetic neurones. The Krebs' solution was maintained at 37 0 C and continually gassed with carbon dioxide. Increases in tissue isometric force were measure using Grass FT03C force displacement transducers and recorded on a Gould BD-212 pen recorder.

A force of 1.0g was applied to each preparation and re-established twice during a subsequent period of 30 minutes. During this period, tissues were exposed to pargyline (500 pM) to irreversibly inhibit monoamine oxidase and to phenoxybenzamine (0.1 M) to inactivate cqt-adrenoceptors. At the end of the 30 minutes, the inhibitors were removed by several changes of the organ bath Krebs' solution.

Agonist activity was assessed by simulative additions of the test compound, its concentration being increased in 0.5 logl0 unit increments until further additions caused no further change in tissue force. In each experiment, the activity of the test compound was compared to the activity of 5-HT. Activity was expressed in terms of the p(A 50 (-log 10 M] where M is the molar concentration of agonist required to produce half the maximum effect). Where the compounds were found to be antagonists, the results are expressed as pKb. The results obtained for the compounds of Synthetic Examples 1 to 19 and 21 to 28 are shown in Table 1.

SUBSTITUTE SHEET (RULE 26) I- -e WO 95/20588 WO 9520588PCTIGB95/00)142 Table I Example 1 (trans) I (cis) 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24~ 26 27 28 pA 50 (az) 6.42 (0.78) 5.8 (0.76) 5,72 (0.09) pKb 5.72 6.05 5.57 6.77 7.18 5.03 5.25 4.95 6.23 4,85 (0.38) 6.25 (0.52) 5.15 (0.29) 6.62 6.02 5.73 5.44(0.16) 6.15(0.72) 5.21(0.48) 5.90 4.78 5.41 3.12 5.18 SUBSTITUTE SHEET (RULE 26) I P IOPFI(\AIpDB\1462O9$.346- 15/12/97 -44- B Calf Caudate Assay Compounds of formula prepared in Synthetic Examples 1 to were further tested for their activity as agonist for the "5-HT-like" receptor mediating smooth muscle contraction by the following method.

Membranes were prepared from homogenates of calf caudate nucleus. Competition binding studies were performed with 3.5nM [H]-5HT (approx. 25Ciml in the presence of 151M mesulergine and 15/tM 8-OH-DPAT, using 5 mg wet weight ml' of membranes in a total volume of 1 ml per tube. Binding data was fitted to a four parameter logistic function to obtain estimates of pIC 5 o. These were converted to pK: values using the Cheng-Prussof equation.

The results obtained for the compounds of Synthetic Examples 1 and 2 are shown in Table 2.

S Table 2 Example Activity P[Asol 1 7.8 20 2 7.05 p.

0 Throughout this specification and the claims which follow, unless the context requires SI otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

"T r' r.

Q

I,

Claims (13)

1. A compound of formula (I) H N W (1) (CH2)n NRR 1 wherein R and R 1 are each independently hydrogen or C1-4 alkyl or R and R 1 are linked to form an azetidine ring; A is C 3 6 cycloalkyl or C 1 -3 alkyl-C 3 -6 cycloalkyl; n is an integer of from 0 to 3; W is a group or (ii): Y Y (ii) wherein R2 is hydrogen or C1-4 alkyl; SX is -NH- or -CH2-; Y is oxygen or sulphur; and the chiral centre is in its or form or is a mixture thereof in any proportions; and salts, solvates and physiologically functional derivatives thereof. (i2. A compound of foula according to claim 1 wherein: Sand R are each indepen tly hydrogen or -4 alkyl andalky X is -NH- or -CH 2 Y is C3-6oxygen or sulphur; and the chiral centre is in its or form or is a mixture thereof in any proportions; and salts, solvates and physiologically functional derivatives thereof.

2. A compound of formula according to claim 1 wherein: R and R 1 are each independently hydrogen or C 1 4 alkyl and A is C 3 6 cycloalkyl; and salts, solvates and physiologically functional derivatives thereof. v I LI ~LIL I.-

3. A compound of formula (la): H Wa (CH 2 (Ia) NRaRa 1 wherein Ra and Ra 1 are each independently hydrogen or C1-4 alkyl; n is an integer of from 0 to 3; Wa is a group or group (ii): y Y NR2 X R2N wherein R 2 is hydrogen or C1- 4 alkyl; *and the chiral centre is in its or form or is a mixture thereof in any proportions; and salts, solvates and physiologically functional derivatives thereof.

4. A compound of formula or (la) according to any of claims 1 to 3 wherein W Xis or(i) I Y is oxygen or sulphur; and the chiral centre is in its or form or is a mixture thereof in any proportions; and salts, solvates and physiologically functional derivatives thereof. 4. A compound of formula or (la) according to any of claims 1 to 3 wherein W is a group (i) L 47 (0) and X, Y, and R2 are as defined in claim 1. A compound of formula or (Ia) according to any of claims i to 4 wherein Y is oxygen.

6. A compound of formula or (1a) according to any of claims 1. to 5 wherein X is

7. A compound of formula according to claim 1 selected from: 4-3: as--mioycou 1l-H-indol-5-ylmethyl]-(4S)oxazolidin-2-one. acetate. 4-[3-(cis-3-aminocyclobutyl)- 1H-indol-5-ylmethyl]-(4S)oxazolidin-2-one acetate. 4-[3-(trans-3-dimethylan-inocyclobutyl)- 1H-indol-5-ylmethyl]-(4S)oxazolidin- 2-one. 4-[3-(trans-3-dimethylaminocyclobutyl)-I--indol-5-ylmethyl]-(4R)oxazolidini- ease*:2-one. :4-[3-(trans,-3-dimethylamrinocyclobutyl)- 1H-indol-5-ylmethyl]-3-meth-yl(4S)- oxazolidin-2-one. -[3-(tans-3-dimethylaminocyclobutyl)- 1H-indol-5-ylmethyl]oxazolidin-2-one. 4-[3 -(trans-3-dimethylaminocyclobut- 1-ylmetliyl)- (4S)oxazolidin-2-one. 4-[3-(trans-3-methylaminocyclobutyl)- 1H-indol-5-ylmethlyl]-(4S)oxazolidin-2- one. 4-[3-(trans-3-dimethylaminocyclobutyl)- 1H-indol-5-ylmethyl]-3-methyl(4R) oxazolidin-2-one. I 48 4-[3-(cis-3-dimethylaminocyclobutyl- 1H-indol-5ylmethyl]-(4S)oxazolidin-2- one. (S)-2-(5-(2-Oxo-4-oxazolidinylmethyl)- 1H-indol-3-yl)cyclopropylamine. and salts, solvates and physiologically functional derivatives thereof.

8. A compound according to claim 7 which is 4-[3-(trans-3- dimethylaminocyclobutyl)- IH-indol-5-ylmethyl]-4(S)oxazolidin-2-one or a physiologically acceptable salt, solvate or physiologically functional derivative thereof.

9. A pharmaceutical composition comprising as active ingredient at least one compound of formula or as defined in any of Claims 1 to 8 and/or a pharmacologically acceptable salt or solvate thereof together with at least one pharmaceutically acceptable carrier or excipient.

10. A method for the preparation of medicament for the prophylaxis or treatment of a clinical condition for which a "5-HT 1 -like" receptor agonist is indicated comprising the step of bringing a compound of formula or (la) according to any of claims 1 to 8 into a form suitable for administration.

11. A method for the prophylaxis or treatment of a clinical condition in a mammal, for example, a human, for which a "5-HT 1 -like" receptor agonist is indicated which comprises administering a compound of fonnula or (Ia) according to any of claims 1 to 8 in an effective amount.

12. A method according to claim 1lwherein the clinical condition is migraine.

13. A process for the preparation of a compound of formula which process comprises: a) reacting a compound of formula (II) 7i'' c, 49 I (II) w W (CH 2 )n wherein W and n are as defined in Claim 1 with a compound of formula (III) NHZ H A (IlI) O 0 wherein Z is a benzyloxycarbonyl group and then removing the benzyloxycarbonyl group to give a compound of formula wherein R R 1 H and optionally converting that compound into a compound of formula wherein R and/or R 1 is C1- 4 alkyl by N-alkylation. or b) reacting a compound of formula (II) with a compound of formula (IV) OMe AH (IV) wherein BOC is tertiary butoxy carbonyl, to give a compound of formula wherein R=R 1 H and optionally converting that compound into a compound of formula wP lein R and/or R 1 is C 1 4 alkyl by N- alkylation; *f r 50 or c) when it is desired to prepare a compound wherein A is a cyclopropyl group, reacting a compound of formula (11) with a compound of formula (V) 0 NHBOC r r o 9 o o e o wherein BOC is tertiary butoxycarbonyl to give a compound of formula wherein R=R 1 =H and optionally converting that compound into a compound of formula wherein R and/or R 1 is C1- 4 alkyl by N- alkylation. DATED this 16th day of December 1997 The Wellcome Foundation By DAVIES COLLISON CAVE Patent Attorneys for the Applicant N I oPAM rIM'DI\A412 95.346 11412/1! Abstract Compounds of formula (I) (CH 2 wherein R and R 1 are hydrogen, C-4 alkyl or are linked to form a ring, A is a cycloalkyl or alkyl-cycloalkyl group, 15 n is an integer from 0 to 3, W is a group or (ii): 9s*' 0* 0 wherein R 2 is hydrogen or C. 4 alkyl; X is -NH- or -CH 2 Y is oxygen or sulphur; and the chiral centre is in its or form or is a mixture thereof in any proportions; and salts, solvates and physiologically functional derivatives thereof; are useful in treating clinical conditions for which a "5-HT,-like" receptor agonist is indicated. J~L- l '4t L L- INTERNATIONAL SEARCH REPORT intfl. l ApplIcaton No SPCT/GB 95/00142 A. CLASSIFICATION OF SUlJIljCI MA''IIKR IPC 6 C07D413/06 A61K31/40 C07D403/06 C07D401/06 C07D209/14 C07D213/06 According to Intcmatonal Patent Cassfication (IPC) or to hoth national classification and IPC B. FIliI.DSSli!ARCIIE1D Minimum documcntaton searched (classification system followed by classification symbols) IPC 6 C07D A61K Documentation searched other than mnrumum documcntation to the extent that such documents are included in the fields searched llcctronic data base consulted during the international search (name of data base and, where practical, search terms used) C. DOCUMIiNTS CONSII)iRHD TO Ili RIl.IVANT Category Citation of document, with indicaton, where appropnate, of the relevant passages Relevant to claim No. A WO,A,91 18897 (THE WELLCOME FOUNDATION 1,9 LTD) 12 December 1991 cited in the application see claims A EP,A,O 313 397 (THE WELLCOME FOUNDATION 1,9 LTD) 26 April 1989 cited in the application see claims P,X WO,A,94 02477 (MERCK SHARP DOHME LTD.) 3 1,9 February 1994 complete document Further documents are listed in the continuation of box C. Patent family members are listed in annex. SSpecial categories of cited documents: T' later document published after the international filing date or priority date and not in conflict with the application but A' document defining the gcncral state of the art which is not cited to understand the pnnciple or theory underlying the considcred to he of particular relevance invention earlier document hut published on or after the international document of particular relevance; the claimed inventon filing date cannot he considered novel or cannot he considered to document which may throw doubts on pnonty claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot he considered to involve an inventive step when the document referrng to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published pnor to the intemauonat filing date hut in the art. later than the pority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 28 February 1995 03. Name and mailing address of the ISA Authonzed officer liuropean Patent Office, 5818 Patentlaan 2 NI.- 2280 IV Ri)swilk T'cl 31-70) 340-2040, 31 651 cponi, Van Bi len, H Fax:

31-70) 340-3016 Form PCT!ISA.210 (second sheet) (July 1992) cl-- 1 I I -C j INTERNATIONAL SEARCH REPORT .rnalonal application No, PCT/GB 95/00142 Box I Observations where certain claims were found unsearchable (Continuation of item I or first sheet) This ificernational search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: Although claim 13 and 14 are directed to a method of treatment of (diag- nostic method practised on) the human/animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. O As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. D As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. O No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest IO The additional search fees were accompanied by the applicant's protest. No piotest accompanied the payment of additional search fees. I I Form PCT/ISA/210 (continuation of first sheet (July 1992) Into, onul AppliCAtion No INTE RNATIONAL SEARCH REPORT IPCT/GB 95/00142 Patent document I Publication IPatent family I Publication cited in search report date Imember(s) Idate W0-A-9118897 12-12-91 AU-B- 646871 10-03-94 AU-A- 7957091 31-12-91 EP-A- 0486666 27-05-92 EP-A- 0636623 01-02-95 JP-T- 5502679 13-05-93 NZ-A- 238424 23-12-93 EP-A-0313397 26-04-89 AU-A- 2418188 27-04-89 OE-A- 3881472 08-07-93 DE-T- 3881472 16-12-93 ES-T- 2054825 16-08-94 JP-A- 1146882 08-06-89 US-A- 5225431 06-07-93 WO-A-9402477 03-02-94 AU-B- 4578593 14-02-94 rorrn PCT'ISAJ2II (patent family annex) (July 1992)